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Caplacizumab induces rapid response for acquired TTP
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Caplacizumab induced a faster response time than placebo among patients with acquired thrombotic thrombocytopenic purpura, a rare blood-clotting disorder, according to phase 2 study results published in The New England Journal of Medicine.
However, caplacizumab (Ablynx) — an anti-von Willebrand factor humanized single-variable domain immunoglobulin — also appeared associated with an increased tendency toward bleeding.
Acquired thrombotic thrombocytopenic purpura (aTTP) leads to extensive micro-clot formations in small blood vessels and damage to organs such as the heart, brain and kidneys.
Mortality from aTTP is high at almost 20%, with a vast majority of deaths occurring within 2 weeks post-diagnosis, according to data from the drug’s manufacturer.
Further, about 36% of patients suffer from recurrences after initial treatment with plasma exchange and immunosuppressive treatments, the current standard of care for this indication.
“Treatment of aTTP with plasma exchange and immunosuppressive therapy takes time to achieve resolution of the disease,” Flora Peyvandi, MD, PhD, director of the department of internal medicine at IRCCS Maggiore Hospital at University of Milan in Italy, and colleagues wrote. “Even when patients have a response to therapy, they are at risk for further microvasculature thrombosis, which is unpredictable in its onset, severity and outcome.”
Peyvandi and colleagues of the TITAN study compared caplacizumab to placebo during plasma exchange and for 30 days afterward to evaluate the potential for the drug in treatment of aTTP.
Time to response served as the primary endpoint. Secondary endpoints included relapse, exacerbation (recurrent thrombocytopenia), complete remission, duration and volume of plasma exchange, mortality and safety.
The investigators enrolled 75 patients with aTTP between October 2010 and January 2014. After that time, the sponsor stopped enrollment prematurely because of recruitment challenges.
Researchers randomly assigned 36 patients to receive 10 mg daily caplacizumab and 39 to placebo.
Most of the patients (n = 69) had not undergone a plasma exchange prior to enrollment. Among these patients, the median time to response was 3 days (95% CI, 2.7-3.9) in the caplacizumab group compared with 4.9 days (95% CI, 3.2-6.6) in the placebo arm.
For the six patients who had undergone a plasma exchange prior to enrollment, the difference was even greater, with a median time to response of 2.4 days (95% CI, 1.9-3) in the caplacizumab arm and 4.3 days (95% CI, 2.9-5.7) in the placebo group.
Overall, this conferred a 39% reduction in the median time to response for those patients treated with caplacizumab (event rate ratio = 2.2; 95% CI, 1.28-3.78).
A post-hoc analysis of 58 patients with baseline ADAMTS13 activity below 10% indicated the median time to response was 3 days (95% CI, 2.7-4.3) with caplacizumab and 4.6 days (95% CI, 3-5.9) with placebo (event rate ratio = 1.63; 95% CI, 0.92-2.92).
Three patients in the caplacizumab group had an exacerbation compared with 11 patients in the placebo arm.
Relapse occurred in eight patients in the caplacizumab group within 1 month of stopping the study drug. Seven of those patients had ADAMTS13 activity that remained below 10%, meaning there was likely unresolved autoimmune activity.
There were more common mild-to-moderate bleeding adverse events in the caplacizumab group than in the placebo group (54% vs. 38%). Two patients in the placebo group died compared with none in the caplacizumab arm.
“Caplacizumab, through rapid blocking of von Willebrand factor-mediated platelet aggregation, prevents further platelet aggregation more rapidly than conventional treatment alone, which could potentially prevent short- and long-term end-organ injury due to ischemia,” the researchers concluded. – by Anthony SanFilippo
Disclosure: This study was funded by Ablynx. Peyvandi reports grant and other support from Ablynx during the conduct of the study. She also reports grant support or personal fees from Alexion, Baxter, Bayer, Biotest, CSL Behring, Grifols, Kedrion Biopharma, LFB, Novo Nordisk, Roche and Sobi outside the submitted work. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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